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Hemolytic Disease of Newborn Treatment & Management

  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Ted Rosenkrantz, MD  more...
Updated: Jan 02, 2016

Medical Care

Management of maternal alloimmunization

As a rule, serial maternal antibody titers are monitored until a critical titer of 1:32, which indicates that a high risk of fetal hydrops has been reached. At this point, the fetus requires very intense monitoring for signs of anemia and fetal hydrops. In Kell alloimmunization, hydrops can occur at low maternal titers because of suppressed erythropoiesis, and, thus, a titer of 1:8 has been suggested as critical. Hence, delta-OD 450 values are also unreliable in predicting disease severity in Kell alloimmunization.[38]

Maternal titers are not useful in predicting the onset of fetal anemia after the first affected gestation. Large differences in titer can be seen in the same patient between different laboratories, and a newer gel technique produces higher titer results than the older tube method. Therefore, standard tube methodology should be used to determine critical titer, and a change of more than 1 dilution represents a true increase in maternal antibody titer. For all the antibodies responsible for hemolytic disease of the newborn (HDN), a 4-fold increase in any antibody titer is typically considered a significant change that requires fetal evaluation.[39]

When indicated, amniocentesis can be performed as early as 15 weeks' gestation (rarely needed in first affected pregnancy before 24 weeks' gestation) to determine fetal genotype and to assess the severity. Maternal and paternal blood samples should be sent to the reference laboratory with amniotic fluid sample to eliminate false-positive results (from maternal pseudogene or Ccde gene) and false-negative results (from a rearrangement at the RHD gene locus in the father).

Fetal Rh-genotype determination in maternal plasma has become routine in many European countries and is being offered in the United States.[40] Fetal cell-free DNA accounts for 3% of total circulating maternal plasma DNA, is found as early as 38 days of gestation, and is derived from apoptosis of the placental cytotrophoblast layer. It is subjected to real-time PCR for the presence of RHD gene–specific sequences and has been found to be accurate in 99.5% of cases. The SRY gene (in the male fetus) and DNA polymorphisms in the general population (in the female fetus) are used as internal controls to confirm the fetal origin of the cell-free DNA.[16] A panel of 92 SNPs is compared between maternal sample from buffy coat and plasma. A difference of more than 6 single nucleotide polymorphisms confirms presence of fetal DNA and the validity of the test in a female fetus.[40]

Unfortunately, cell-free fetal DNA testing for determining the genotype for other red blood cell antigens such as E and Kell is not yet available in United States.

Serial amniocentesis is begun at 10-14 day intervals to monitor the severity of the disease in the fetus. All attempts should be made to avoid transplacental passage of needle which can lead to fetomaternal hemorrhage (FMH) and a further rise in antibody titer. Serial delta-OD 450 values are plotted on the Queenan chart or the extended Liley chart to evaluate the risk of fetal hydrops. Early ultrasonography is performed to establish correct gestational age. Frequent ultrasonographic monitoring is also performed to assess fetal well-being and to detect moderate anemia and early signs of hydrops.

The peak systolic middle cerebral artery (MCA) Doppler velocity has proved to be a reliable screening tool to detect fetal anemia and has replaced amniocentesis. The MCA is easily visualized with color-flow Doppler; pulsed Doppler is then used to measure the peak systolic velocity just distal to its bifurcation from the internal carotid artery. Because the MCA velocity increases with advancing gestational age, the result is reported in multiples of median (MOMs). In recent studies, the sensitivity for detection of moderate and severe fetal anemia has been proven to be 100%, with a false-positive rate of 10% at 1.5 MOM.[41] It has been shown to reduce the need for invasive diagnostic procedures such as amniocentesis and cordocentesis by more than 70%.[41]

MCA Doppler studies can be started as early as 18 weeks' gestation but are not reliable after 35 weeks' gestation.[42]  It has also been used to time the subsequent fetal transfusion and to diagnose anemia from multiple causes, such as in twin-twin transfusion. The MCA slope from 3-weekly readings is now used to predict fetal risk for severe anemia (see the image below).[43]

Slopes for peak systolic velocity in middle cerebr Slopes for peak systolic velocity in middle cerebral artery (MCA) for normal fetuses (dotted line), mildly anemic fetuses (thin line), and severely anemia fetuses (thick line).

With acquisition of experience in performing MCA Doppler study, serial amniocentesis for detecting fetal anemia has been used to lesser extent.[44]

During the period when intrauterine peritoneal transfusion was the only means of treatment, newborns were routinely delivered at 32 weeks' gestation. This approach resulted in a high incidence of hyaline membrane disease and exchange transfusions. With the advent of intravascular transfusion (IVT) in utero, the general approach to the severely affected fetus is to perform IVT as required until 35 weeks' gestation, with delivery planned at term. Establishment of lung maturity is difficult in these fetuses because of contamination of amniotic fluid with residual blood during transfusion; however, if delivery is planned prior to 34 weeks' gestation, maternal steroid administration to enhance fetal lung maturity is indicated.

In addition, excess amniotic fluid bilirubin levels cause false elevation on the fluorescence depolarization TDx fetal lung maturity test, version II (TDX-FLMII); therefore, other tests to determine fetal lung maturity should be used, such as infrared spectroscopy, lamellar body count, phosphatidylglycerol quantitation or lecithin/sphingomyelin (L/S) ratio.

Liley first described intraperitoneal transfusion (IPT) in 1963. A Tuohy needle is introduced into the fetal peritoneal cavity under ultrasonographic guidance. An epidural catheter is threaded through the needle. A radiopaque medium is injected into the fetal peritoneum. The proper placement is confirmed by delineation outside of bowel or under the diaphragm or by diffusion in fetal ascites. Packed RBCs at Hct of 75-80% that are CMV-negative, less than 4-days-old, group O, Rh-negative, Kell-negative, leukoreduced, irradiated with 25 Gy to prevent graft versus host disease, and cross-matched with maternal serum are injected in 10-mL aliquots to a volume calculated by the following formula:[1]

IPT volume = (gestation in wk - 20) X 10 mL

Residual Hb in the fetus is estimated to allow for proper spacing of IPT and selection of gestation of delivery by the following formula:

Hb g/dL = 0.85/125 X a/b X 120 - c/120

In the formula, a is the amount of donor RBC Hb transfused, b is the estimated fetal body weight, and c is the interval in days from the time of transfusion to the time of donor Hb estimation.

IPT is repeated when the fetal Hb is estimated to have dropped to 10 g/dL. Usually, a second IPT is performed 10 days after the first transfusion in order to raise the Hb above 10 g/dL. Then another transfusion is performed every 4 weeks until the time of planned delivery at 34-35 weeks' gestation. Fetal diaphragmatic movements are necessary in order for absorption of RBC to occur. This approach is of no value for a moribund nonbreathing fetus. Maternal complications include infection and transplacental hemorrhage, whereas fetal complications are overtransfusion, exsanguination, cardiac tamponade, infection, preterm labor, and graft versus host disease. Survival rates after IPT approached approximately 75% with the help of ultrasonography.

Direct IVT has become a preferred route of fetal intervention because of the higher rate of complications and limited effectiveness of IPT in a hydropic fetus. Rodeck first successfully performed IVT in 1981. With ultrasonographic guidance, a needle is introduced into an umbilical vein at the cord insertion into the placenta or into its intrahepatic portion, and a fetal blood sample is obtained. The blood sample is confirmed to be of fetal origin by rapid alkaline denaturation test. All the relevant fetal tests (eg, blood type, direct antibody test, reticulocyte count, platelet count, Hb level, Hct level, serum albumin level, erythropoietin level) are performed. If the Hb level is less than 11 g/dL or if the Hct level is less than 30%, an IVT is started. The position of the needle is confirmed by noting the turbulence in the fetal vessel on injection of saline. The fetus is frequently paralyzed with pancuronium in order to prevent the displacement of the needle by fetal movements.

The transfusion is performed in 10-mL aliquots to a volume of approximately 50 mL/kg estimated body weight using ultrasonography or until an Hct level of 40% is reached. The procedure is promptly discontinued if cardiac decompensation is noted on ultrasonography findings. Severely anemic fetuses do not tolerate acute correction of their Hct to normal values, and the initial Hct should not be increased by more than 4-fold at the time of first IVT. They should then be monitored every 2-7 days. The IVT is repeated when it reaches a value that reflects critical anemia in the fetus. A loss of 1% of transfused cells per day can be anticipated.[16]

Some centers perform repeat transfusion at intervals of 10 days, 2 weeks, and every 3 weeks. Others transfuse based on an anticipated decline in fetal hemoglobin of 0.4 g/dL/day, 0.3 g/dL/day, and 0.2 g/dL/day for first, second, and third transfusion intervals, respectively.[45] The peak systolic MCA velocity has been used to time the second transfusion, with a threshold of 1.32 MOM.[46] After the first intrauterine transfusion, the presence of red blood cells with adult hemoglobin suppress erythropoiesis and improve oxygen delivery, which is responsible for the poor correlation between peak MCA velocity and severity of fetal anemia.

In addition to the complications of IPT, transient fetal bradycardia, cord hematoma, umbilical vein compression, and fetal death have been reported during IVT. However, IVT has many advantages, including immediate correction of anemia and resolution of fetal hydrops, reduced rate of hemolysis and subsequent hyperinsulinemia, and acceleration of fetal growth for nonhydropic fetuses who are often growth retarded. IVT is the only intervention available for moribund hydropic fetuses and those with anterior placenta. The risk of fetal loss is about 0.8% with IVT versus 3.5% per procedure for IPT, and the overall survival rate is 88%.

Recently washed maternal RBCs have been successfully used as a source of antigen-negative RBCs in the event of rare incompatibility but also have been routinely used because of benefits such as decreased risk for sensitization to new red cell antigens, a longer circulating half-life being fresh, and decreased risk of transmission of viral agents.[47] Mother can donate a unit of red cells after the first trimester.

In the event of pulmonary immaturity and delta-OD 450 in the affected zone of the Queenan curve, oral administration of 30 mg of phenobarbital to the mother 3 times per day, followed by induction in one week, reduces the need for exchange transfusion in the affected neonate.[48] Excellent algorithms for management of the first affected pregnancy and the pregnancy in a mother with previously affected fetus are outlined in a review by Moise (see the images below).[49]

Management of first affected pregnancy. Management of first affected pregnancy.
Management of pregnant women with previously affec Management of pregnant women with previously affected fetus.

Initial attempts to suppress Rh antibody production with Rh hapten, Rh-positive RBC stroma, and administration of promethazine were unsuccessful. Extensive plasmapheresis with partial replacement using 5% albumin and intravenous immunoglobulin (IVIG) or the administration of IVIG at 1 g/kg body weight weekly has been shown to be moderately effective. The mechanism of action appears to be blockage of Fc receptors in the placenta, reducing antibody transport across to the fetus, Fc receptors on the phagocytes in the fetal reticuloendothelial system, and feedback inhibition of maternal antibody synthesis.

However, these techniques only postpone the need for percutaneous umbilical blood sampling (PUBS) and IVT until 20-22 weeks' gestation, when these procedures can be performed at a more acceptable risk. A review of IVIG use shows its usefulness in preventing the onset of fetal hydrops and in delaying the need for intrauterine transfusion (IUT).[50] Thus, a combined approach of plasmapheresis that starts at 12 weeks' gestation 3 times in that week, followed by IVIG at a loading dose of 2 g/kg after the third plasmapheresis, and then continued IVIG 1 g/kg/wk until 20 weeks' gestation has been suggested for at-risk fetuses prior to 20 weeks' gestation and can also be used later in gestation if IVT cannot be performed or if hydrops is unresponsive to IVT.

One report indicated that treatment of fetuses with severe alloimmunization using IVT combined with fetal IVIG therapy at 1 g/kg/dose starting from the third IVT helped in reducing the frequency of IVT and improving signs of hydrops.[51] A case report shows successful treatment of severe anemia and hydrops in a fetus with alloimmunization due to anti-M antibody with fetal intraperitoneal IVIG injections 2 g/kg given weekly starting 30 weeks.[52] However, this was a case report, and a randomized controlled trial is needed before this can become standard of care.

Similar regimens of tests and treatment are used in the management of pregnancies affected by nonRhD alloimmunization, such as anti-Rhc, anti-K (K1), and anti-M. Once the mother is diagnosed with an antibody associated with hemolytic disease, an indirect Coombs titer is performed, along with paternal testing for involved antigen and zygosity. Maternal titers are repeated (monthly until 28 weeks' gestation and then every 2 wk) until a threshold for fetal anemia is reached (1:8 for Kell and 1:32 for rest).

Fetal antigen typing is performed via amniocentesis or cell-free fetal DNA in maternal plasma if the father is found to be heterozygous (100% for K1, 65% for M). When the fetus is known to be antigen positive, surveillance for severe fetal anemia is performed, with weekly MCA Doppler screening as early as 16-18 weeks and IUT is carried out if it exceeds 1.5 MOM with a delivery by 38 weeks' gestation.[53]

Maternal alloantibodies to paternal leukocytes have been shown to result in Fc blockade and to reduce the severity of fetal hemolytic anemia. This may be used in the future.

Management of the sensitized neonate

Mild hemolytic disease accounts for 50% of newborns with positive direct antibody test results. Most of these newborns are not anemic (cord hemoglobin [Hb] >14 g/dL) and have minimal hemolysis (cord bilirubin < 4 mg/dL). Apart from early phototherapy, they require no transfusions. However, these newborns are at risk of developing severe late anemia by 3-6 weeks of life. Therefore, monitoring their Hb levels after hospital discharge is important.

Moderate hemolytic disease accounts for approximately 25% of affected neonates. Moderate hemolytic disease of newborn is characterized by moderate anemia and increased cord bilirubin levels. These infants are not clinically jaundiced at birth but rapidly develop unconjugated hyperbilirubinemia in the first 24 hours of life. Peripheral smear shows numerous nucleated RBCs, decreased platelets, and, occasionally, a large number of immature granulocytes. These newborns often have hepatosplenomegaly and are at risk of developing bilirubin encephalopathy without adequate treatment. Early exchange transfusion with type-O Rh-negative fresh RBCs with intensive phototherapy is usually required. Use of IVIG in doses of 0.5-1 g/kg in a single or multiple dose regimen have been able to effectively reduce need for exchange transfusion.[54]

A prospective randomized controlled study has shown early high-dose IVIG 1 g/kg at 12 hours of age to reduce duration of phototherapy and hospital stay and to prevent exchange transfusion in neonates with moderate-to-severe Rh isoimmunization.[55] These newborns are also at risk of developing late hyporegenerative anemia of infancy at 4-6 weeks of life. However, one randomized double-blind placebo-controlled trial failed to show the benefit of prophylactic IVIG therapy 0.75 g/kg within 4 hours of age in severely affected neonates who were treated with intrauterine transfusion for Rh isoimmunization.[56]

Severe hemolytic disease accounts for the remaining 25% of the alloimmunized newborns who are either stillborn or hydropic at birth. The fetal hydrops is predominantly caused by a capillary leak syndrome due to tissue hypoxia, hypoalbuminemia secondary to hepatic dysfunction, and high-output cardiac failure from anemia. About half of these fetuses become hydropic before 34 weeks' gestation and need intensive monitoring and management of alloimmunized gestation as described earlier. Mild hydrops involving ascites reverses with IVTs in only 88% of cases with improved survival but severe hydrops causing scalp edema and severe ascites and pleural effusions reverse in 39% of cases and are associated with poor survival.

Management of ABO incompatibility

Management of hyperbilirubinemia is a major concern in newborns with ABO incompatibility. The criteria for exchange transfusion and phototherapy are similar to those used in Rh alloimmunization. IVIG has also been very effective when administered early in the course. Tin (Sn) porphyrin a potent inhibitor of heme oxygenase, the enzyme that catalyzes the rate-limiting step in the production of bilirubin from heme, has been shown to reduce the production of bilirubin and reduce the need for exchange transfusion and the duration of phototherapy in neonates with ABO incompatibility.

Tin or zinc protoporphyrin or mesoporphyrins have been studied in newborns. They must be administered intramuscularly in a dose based on body weight, and their effectiveness appears to be dose related in all gestations.[57] Their possible toxic effects include skin photosensitization, iron deficiency, and possible inhibition of carbon monoxide production. Their use in Rh hemolytic disease of newborn has not been reported. Their routine use cannot be recommended yet because of lack of long-term safety data.

Contributor Information and Disclosures

Sameer Wagle, MBBS, MD Consulting Staff, Division of Neonatology, Northwest Medical Center of Springdale and Willow Creek Women’s Hospital

Sameer Wagle, MBBS, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association

Disclosure: Nothing to disclose.


Prashant G Deshpande, MD Attending Pediatrician, Department of Pediatrics, Christ Hospital Medical Center and Hope Children's Hospital; Assistant Clinical Professor of Pediatrics, Midwestern University

Prashant G Deshpande, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Telemedicine Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David A Clark, MD Chairman, Professor, Department of Pediatrics, Albany Medical College

David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical and Dental Associations, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Oussama Itani, MD, FAAP, FACN Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center

Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American Association for Physician Leadership, American Heart Association, American College of Nutrition

Disclosure: Nothing to disclose.

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Liley curve. This graph illustrates an example of amniotic fluid spectrophotometric reading of 0.206, which when plotted at 35 weeks' gestation falls into zone 3, indicating severe hemolytic disease.
Modified Liley curve for gestation of less than 24 weeks showing that bilirubin levels in amniotic fluid peak at 23-24 weeks' gestation.
Queenan Curve: Modified Liley curve that shows delta-OD 450 values at 14-40 weeks' gestation.
Slopes for peak systolic velocity in middle cerebral artery (MCA) for normal fetuses (dotted line), mildly anemic fetuses (thin line), and severely anemia fetuses (thick line).
Management of first affected pregnancy.
Management of pregnant women with previously affected fetus.
Table. Comparison of Rh and ABO Incompatibility
Characteristics Rh ABO
Clinical aspects First born 5% 50%
Later pregnancies More severe No increased severity
Stillborn/hydrops Frequent Rare
Severe anemia Frequent Rare
Jaundice Moderate to severe, frequent Mild
Late anemia Frequent Rare
Laboratory findings Direct antibody test Positive Weakly positive
Indirect Coombs test Positive Usually positive
Spherocytosis Rare Frequent
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